There are several different classes of compounds which have serum cholesterol lowering properties. Some of these compounds are inhibitors of the enzyme HMG CoA reductase which is essential in the production of cholesterol, such as mevastatin (disclosed in U.S. Pat. No. 3,983,140), lovastatin also referred to as mevinolin (disclosed in U.S. Pat. No. 4,231,938), pravastatin (disclosed in U.S. Pat No. 4,346,227) and velostatin also referred to as synvinolin (disclosed in U.S. Pat. Nos. 4,448,784 and 4,450,171).
Other compounds which lower serum cholesterol may do so by an entirely different mechanism than the HMG CoA reductase inhibitors. For example, serum cholesterol may be lowered through the use of bile acid sequestrants such as cholestyramine, colestipol, DEAE-Sephadex and poly(diallylmethylamine) derivatives (such as disclosed in U.S. Pat. Nos. 4,759,923 and 4,027,009) or through the use of antihyperlipoproteinemics such as probucol and gemfibrozil which apparently lower serum lower density lipoproteins (LDL) and/or converts LDL into high density lipoproteins (HDL).
U.S. Pat. No. 4,759,923 mentioned above discloses that poly(diallylmethylamine) derivatives which are bile salt sequestrants may be used in conjunction with drugs which reduce serum cholesterol by mechanisms other than sequestration, such as clofibrate, nicotinic acid, probucol, neomycin, p-aminosalicylic acid or mevinolin (also referred to as lovastatin).
Other known cholesterol lowering agents include derivatives of nicotinic acid, namely 5-methylpyrazine-carboxylic acid 4-oxide (acipimox), 4,5-dihydro-5-methyl-4-oxo-5-phenyl- 2-furancarboxylic acid (acifran) and nicotinic acid N-oxide-2-t-butyl-4-cyclohexylphenyl ester, the latter being disclosed in Drug. Fut., 1987, 12, 349.
Grundy, S. M. "HMG-CoA Reductase Inhibitors for Treatment of Hypercholesterolemia," N. Eng. J. Med. Vol. 319 No. 1 pp 24-33, discloses that pravastatin by itself and nicotinic acid by itself are known cholesterol lowering drugs.
At page 28, column 2, Grundy discloses that combinations of lovastatin and gemfibrozil may be associated with an increased frequency of drug induced myopathy.
At page 29, lines 7 to 11, Grundy discloses that "recent clinical experience suggests that the combination of lovastatin and cyclosporine, gemfibrozil, or niacin may predispose patients to myopathy and occasionally even to rhabdomyolysis."
At page 30, column 1, starting at the last six lines from the bottom Grundy indicates that "the combination of lovastatin and niacin has not been shown to be safe in a controlled clinical trial."
Physicians' Desk Reference, 44th Ed., 1990, page 1413, reports that severe cases of rhabdomyolysis have been associated in patients receiving lovastatin in combination with either gemfibrozil or lipid-lowering doses of nicotinic acid.
It is now believed that hypertriglyceridemia may be an independent risk factor for coronary artery disease, particularly in vulnerable populations, such as in diabetics. Furthermore, many individuals with hypercholesterolemia also have elevated triglyceride levels (mixed hyperlipidemia). In such cases, a reduction in triglyceride concentrations can also result in the secondary lowering of cholesterol.
It is also known that patients with severe hypertriglyceridemia are at risk for developing pancreatitis.